scholarly journals Lipocalin 2 negatively regulates cell proliferation and epithelial to mesenchymal transition through changing metabolic gene expression in colorectal cancer

2017 ◽  
Vol 108 (11) ◽  
pp. 2176-2186 ◽  
Author(s):  
Se‐Lim Kim ◽  
Soo Teik Lee ◽  
In Suk Min ◽  
Young Ran Park ◽  
Ju Hyung Lee ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Epithelial To Mesenchymal Transition ◽  
Lipocalin 2 ◽  
Mesenchymal Transition ◽  
Metabolic Gene ◽  
Metabolic Gene Expression

scholarly journals Pyrvinium pamoate inhibits cell proliferation through ROS-mediated AKT-dependent signaling pathway in colorectal cancer

2021 ◽  
Vol 38 (2) ◽  
Author(s):  
Wenqian Zheng ◽  
Jinhui Hu ◽  
Yiming Lv ◽  
Bingjun Bai ◽  
Lina Shan ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Signaling Pathway ◽  
Epithelial To Mesenchymal Transition ◽  
Flow Cytometric Analysis ◽  
Inhibitory Effect ◽  
Dependent Manner ◽  
Mesenchymal Transition ◽  
Dependent Signaling Pathway ◽  
Pyrvinium Pamoate

AbstractThe use of the anthelmintic drug pyrvinium pamoate (PP) in cancer therapy has been extensively investigated in the last decade. PP has been shown to have an inhibitory effect in colorectal cancer (CRC), but the underlying mechanism remains elusive. We aimed to investigate the antitumor activity and mechanisms of PP in CRC. In the present study, we used CCK-8 assays, colony formation assays, and western blotting to reveal that PP effectively suppressed CRC cell proliferation and the AKT-dependent signaling pathway in a concentration-dependent and time-dependent manner. Flow cytometric analysis and fluorescence microscopy demonstrated that PP increased intracellular reactive oxygen species (ROS) accumulation. We found that the inhibitory effect of PP on cell proliferation and AKT protein expression induced by PP could be partially reversed by N-acetyl-l-cysteine (NAC), an ROS scavenger. In addition, the results also demonstrated that PP inhibited cell migration by modulating epithelial-to-mesenchymal transition (EMT)-related proteins, including E-cadherin and vimentin. In conclusion, our data suggested that PP effectively inhibited cell proliferation through the ROS-mediated AKT-dependent signaling pathway in CRC, further providing evidence for the use of PP as an antitumor agent.

scholarly journals Leptin, BMI, and a Metabolic Gene Expression Signature Associated with Clinical Outcome to VEGF Inhibition in Colorectal Cancer

2016 ◽  
Vol 23 (1) ◽  
pp. 77-93 ◽  
Author(s):  
Aurélien J.C. Pommier ◽  
Matthew Farren ◽  
Bhavika Patel ◽  
Mark Wappett ◽  
Filippos Michopoulos ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Clinical Outcome ◽  
Gene Expression Signature ◽  
Expression Signature ◽  
Metabolic Gene ◽  
Metabolic Gene Expression ◽  
Vegf Inhibition

Association of colorectal cancer intrinsic subtypes with prognosis, chemotherapy response, deficient mismatch repair, and epithelial to mesenchymal transition (EMT).

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 333-333
Author(s):  
Iris Simon ◽  
Paul Roepman ◽  
Andreas Schlicker ◽  
Josep Tabernero ◽  
Ian Majewski ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Mismatch Repair ◽  
Mutation Frequency ◽  
Epithelial To Mesenchymal Transition ◽  
Molecular Classification ◽  
Chemotherapy Response ◽  
Intrinsic Subtypes ◽  
Mesenchymal Transition

333 Background: Unbiased genome-wide analyses of gene expression patterns have been successfully used for the molecular classification of breast cancer into subtypes that have clear relevance for prognosis and development of treatment plans. For colorectal cancer (CRC), however, a molecular classification is still missing. Methods: Using gene expression data of 188 stage I-IV colorectal cancer (CRC) patients, a molecular subtype classification was developed. The classifier was validated in 543 stage II and III patients and the subtypes were analyzed for correlation to clinical information, mutations in the kinome, known molecular marker status and chemotherapy response. Results: CRC is a heterogeneous disease that consists of at least three major intrinsic subtypes (A-, B-, C-type). The heterogeneity of the intrinsic subtypes is largely based on three biological hallmarks of the tumor: an epithelial-to-mesenchymal transition, deficiency in mismatch repair genes that result in a high mutation frequency associated with MSI, and cellular proliferation. C-type patients have the worst outcome, a mesenchymal gene expression phenotype, and show no benefit from adjuvant chemotherapy treatment. Patients having A-type or B-type tumors have a better clinical outcome, a more proliferative and epithelial phenotype, and benefit from adjuvant chemotherapy. B-type tumors showed a low overall kinome mutation frequency (1.6%), while both A-type and C-type patients harbor a higher mutation frequency (respectively 4.2 and 6.2%), in agreement with their mismatch repair deficiency. Conclusions: We have developed a diagnostic single sample predictor that allows the classification of CRC tumors of different intrinsic molecular subtypes. These subtypes are potentially clinically relevant, as they differ in their underlying biology and clinical outcome and consequently require different treatment strategies. [Table: see text]

MicroRNA regulation of radiation sensitivity in colorectal cancers.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 608-608
Author(s):  
Shushan Rajesh Rana ◽  
Katherine Kelley ◽  
Rebecca Ruhl ◽  
Charles R. Thomas ◽  
Vassiliki Liana Tsikitis ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Cancer Progression ◽  
Epithelial To Mesenchymal Transition ◽  
Locally Advanced ◽  
Radiation Sensitivity ◽  
Colorectal Cancers ◽  
Specific Gene ◽  
Mesenchymal Transition

608 Background: Patients with locally advanced colorectal cancer (T3/T4/Node positive) receive neoadjuvant chemoradiation therapy (CRT) and subsequent surgery. While 10-25% of patients have complete response to CRT, the remaining patients undergo extensive tumor excision that leads to quality of life issues. Response to CRT is an independent predictor of overall survival highlighting the importance of improving CRT response rates. Several tumor intrinsic factors govern responses to CRT including specific gene expression programs. Emerging evidence suggests that microRNAs (miRs) modulate gene expression programs in response to radiation. Moreover, miR-processing machinery is frequently mutated in colorectal cancers (TCGA, 2016 provisional). miRs have been implicated in several pathological processes associated with colorectal cancer progression including cancer stemness and epithelial-to-mesenchymal transition (EMT). In this context, we hypothesized that differential expression of miRs regulates colorectal cancer radiation sensitivity and therefore can be used as a biomarker to predict therapeutic responses to radiation. Methods: To investigate the differences in miR profiles between rectal cancer patients that had either a pathological partial response (PR) or no response (NR), we isolated RNA from FFPE biopsies using the miRvana microRNA isolation kit (Life Technologies). We used the Nanostring miR profiling platform and obtained absolute counts for > 700 human miRs of which ~500 miRs were expressed above detection limits (cut-off of 20 counts after normalization to the top-100 miRs). We performed in vitro gain and loss of studies with miR transfections in human CRC cell lines with RNAimax reagent and used a luminescence-based assay for proliferation (Cell titer glo, Promega). We performed surviving fraction assays by seeding cells on 6 well plate and counting colonies stained with Methylene Blue. Results: We identified seventeen miRs that were differentially expressed. Among the most upregulated in this group, miR-451a, inhibited proliferation and colony formation in 2D and 3D assays in the presence of radiation. Conclusions: Our data suggests miRs may alter cell survival pathways and affect tumor radiosensitivity.

scholarly journals Bidirectional KCNQ1:β-catenin interaction drives colorectal cancer cell differentiation

2017 ◽  
Vol 114 (16) ◽  
pp. 4159-4164 ◽  
Author(s):  
Raphael Rapetti-Mauss ◽  
Viviana Bustos ◽  
Warren Thomas ◽  
Jean McBryan ◽  
Harry Harvey ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Plasma Membrane ◽  
Ion Channel ◽  
Cell Lines ◽  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Disease Free Survival ◽  
Mesenchymal Transition ◽  
Tumor Patient

The K+ channel KCNQ1 has been proposed as a tumor suppressor in colorectal cancer (CRC). We investigated the molecular mechanisms regulating KCNQ1:β-catenin bidirectional interactions and their effects on CRC differentiation, proliferation, and invasion. Molecular and pharmacologic approaches were used to determine the influence of KCNQ1 expression on the Wnt/β-catenin signaling and epithelial-to-mesenchymal transition (EMT) in human CRC cell lines of varying stages of differentiation. The expression of KCNQ1 was lost with increasing mesenchymal phenotype in poorly differentiated CRC cell lines as a consequence of repression of the KCNQ1 promoter by β-catenin:T-cell factor (TCF)-4. In well-differentiated epithelial CRC cell lines, KCNQ1 was localized to the plasma membrane in a complex with β-catenin and E-cadherin. The colocalization of KCNQ1 with adherens junction proteins was lost with increasing EMT phenotype. ShRNA knock-down of KCNQ1 caused a relocalization of β-catenin from the plasma membrane and a loss of epithelial phenotype in CRC spheroids. Overexpression of KCNQ1 trapped β-catenin at the plasma membrane, induced a patent lumen in CRC spheroids, and slowed CRC cell invasion. The KCNQ1 ion channel inhibitor chromanol 293B caused membrane depolarization, redistribution of β-catenin into the cytosol, and a reduced transepithelial electrical resistance, and stimulated CRC cell proliferation. Analysis of human primary CRC tumor patient databases showed a positive correlation between KCNQ1:KCNE3 channel complex expression and disease-free survival. We conclude that the KCNQ1 ion channel is a target gene and regulator of the Wnt/β-catenin pathway, and its repression leads to CRC cell proliferation, EMT, and tumorigenesis.

scholarly journals Cholest-4,6-Dien-3-One Promote Epithelial-To-Mesenchymal Transition (EMT) in Biliary Tree Stem/Progenitor Cell Cultures In Vitro

Cells ◽  
2019 ◽  
Vol 8 (11) ◽  
pp. 1443
Author(s):  
Lorenzo Nevi ◽  
Daniele Costantini ◽  
Samira Safarikia ◽  
Sabina Di Matteo ◽  
Fabio Melandro ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Proliferation ◽  
Epithelial To Mesenchymal Transition ◽  
Biliary Tree ◽  
Telomerase Activity ◽  
Mesenchymal Transition ◽  
Peribiliary Glands ◽  
Emt Markers ◽  
Tree Stem

Human biliary tree stem/progenitor cells (hBTSCs), reside in peribiliary glands, are mainly stimulated by primary sclerosing cholangitis (PSC) and cholangiocarcinoma. In these pathologies, hBTSCs displayed epithelial-to-mesenchymal transition (EMT), senescence characteristics, and impaired differentiation. Here, we investigated the effects of cholest-4,6-dien-3-one, an oxysterol involved in cholangiopathies, on hBTSCs biology. hBTSCs were isolated from donor organs, cultured in self-renewal control conditions, differentiated in mature cholangiocytes by specifically tailored medium, or exposed for 10 days to concentration of cholest-4,6-dien-3-one (0.14 mM). Viability, proliferation, senescence, EMT genes expression, telomerase activity, interleukin 6 (IL6) secretion, differentiation capacity, and HDAC6 gene expression were analyzed. Although the effect of cholest-4,6-dien-3-one was not detected on hBTSCs viability, we found a significant increase in cell proliferation, senescence, and IL6 secretion. Interestingly, cholest-4.6-dien-3-one impaired differentiation in mature cholangiocytes and, simultaneously, induced the EMT markers, significantly reduced the telomerase activity, and induced HDAC6 gene expression. Moreover, cholest-4,6-dien-3-one enhanced bone morphogenic protein 4 (Bmp-4) and sonic hedgehog (Shh) pathways in hBTSCs. The same pathways activated by human recombinant proteins induced the expression of EMT markers in hBTSCs. In conclusion, we demonstrated that chronic exposition of cholest-4,6-dien-3-one induced cell proliferation, EMT markers, and senescence in hBTSC, and also impaired the differentiation in mature cholangiocytes.

Sign in / Sign up

Export Citation Format

Share Document